The present invention relates to a device for controlled release drug delivery, and more particularly to a polyvinyl chloride based controlled release drug delivery device.
In recent years, various drug delivery systems have been developed which provide substantial release of a drug, such as transdermal drug delivery systems. These systems have taken various forms. Thus, for example, it is known in the art to incorporate a drug in a gel by a batch technique. In this technique, a gel-forming composition containing the drug is poured into a tube and then heated to about 110.degree. C. until it sets. The set gel is then sliced to provide individual product units. The prior art batch technique is slow and inefficient, and results in a product which is cosmetically inelegant and subject to syneresis where there is a leaking out of liquid from the gel. This batch technique also suffers from problems of reproducibility, difficulty in controlling the thickness of the product, and difficulty in slicing of the gel.
Another prior art transdermal delivery device has been provided in the form of a pouch containing a backing layer and a transmissive drug release rate controlling membrane, with a chamber therebetween which contains a solution or suspension of drug. If the pouch were to break, there would be an intermediate release of large amounts of drug, that is, there would be a "dumping" of drug.
It is known to prepare a pharmaceutical delivery device from a silicone liquid polymer which is mixed with the drug and then cured with a catalyst to form a biologically acceptable silicone polymer matrix having microsealed compartments throughout which contain the drug, which can be present in a hydrophilic solvent system. The biologically acceptable silicone polymer matrix can be placed in a sealed or unsealed biologically acceptable polymer container made of a material capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate. See, for example, U.S. Pat. Nos. 3,992,518, 3,946,106 and 4,053,580. If the drug is in powder form, large amounts of the drug cannot be employed because a stiff product results. Moreover, care must be taken to avoid poisoning of the catalyst, which can occur due to interactions between the catalyst and drug. For example, amine drugs when present in amounts of, for example, 25% by weight, kill the catalyst and therefore such drugs are not suitable for use in such amounts with silicone liquid polymers. The silicone liquid polymer operation is a costly batch type method which requires a proper mixing of the various ingredients, and it is time constrained once the ingredients are mixed together. The batch silicone liquid polymer method generally results in fixed size product units.
U.S. Pat. No. 4,336,243 discloses a microsealed transdermal nitroglycerin pad comprising a backing which is impervious to nitroglycerin absorption and transport, and a biologically acceptable silicone polymer matrix affixed thereto. The silicone polymer matrix is a cross-linked silicone rubber having microsealed compartments which are formed by in situ crosslinking of the silicone rubber after it is mixed with a hydrophilic solvent system containing the nitroglycerin and a hydrophobic solvent system which enhances nitroglycerin dispersion and transport. The hydrophobic solvent system can be comprised of isopropylpalmitate (IPP), mineral oil, cholesterol or a triglyceride of a saturated coconut oil acid or a mixture thereof. The combined hydrophilic and hydrophobic solvent systems which are incorporated within the matrix are stated to serve the unique purpose of partitioning and enhancing the diffusion of nitroglycerin throughout the matrix. The patent further discloses that a number of materials which are capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate can be used to form a biologically acceptable polymer container. Among the materials disclosed for this purpose is polyvinyl chloride, but no example of the use of polyvinyl chloride is shown in the patent. The polymers which are stated to be suitable for forming thin walls or coatings through which nitroglycerin can pass at a controlled rate are stated to have a durometer hardness of 30 to 100 Shore A, a tensile strength of 500 to 700 psi, an elongation of 100 to 400% and a tear strength of 70 to 100 ppi.
Canadian Pat. No. 930,668 discloses a bandage for administering drugs comprised of a backing member, a pressure sensitive adhesive, and at least one reservoir disposed between the backing member and pressure sensitive adhesive. The reservoir is comprised of a systemically active drug formulation confined within a wall member, the wall member being formed from a drug release rate controlling material. The reservoir can be in the form of discrete microcapsules or distinct reservoir compartments or layers. The reservoir can also be in the form of walled containers having one or more interior drug-containing chambers, as well as solid or gel matrixes having a systemically active drug distributed therethrough. The Canadian patent discloses a wide variety of materials which can be used to form the reservoir. Among the materials mentioned are silicone rubbers, hydrophilic polymers of monoesters of an olefinic acid, polyvinylalcohol, polyvinylacetate, plasticized polyvinylchloride, plasticized nylon, collagen, gelatin, and waxes such as polyethylene wax, oxidized polyethylene wax, hydrogenated castor oil and the like, with the silicone rubbers being preferred. The Canadian patent does not contain any examples showing the use of plasticized polyvinylchloride, and does not show the use of a PVC plastisol.
As is well known, polyvinyl chloride (PVC) is never used alone, but is always mixed with other ingredients before being processed. Polyvinyl chloride appeared at first to be an unpromising resin because it is insoluble in common solvents, cannot be molded without thermal decomposition and turns black in a few days exposure to sunlight. PVC, however, was discovered to form a rubberlike material when dissolved hot in high boiling solvents known as plasticizers and cooled to room temperature. PVC is now available in a number of different physical forms and types, and its manufacture depends on the form desired. Thus, PVC is available as a vinyl latex, a dispersion resin, or a general purpose resin. PVC latexes are true colloidal dispersions of submicrometer particles in water, stabilized by a surfactant system, and need plasticizers in order to form a continuous film. The PVC in a vinyl latex is manufactured by emulsion polymerization.
Dispersion resins are produced by emulsion polymerization and are mixed with liquid plasticizers to form a colloidal dispersion of resin powder in plasticizer. Such dispersions are known as plastisols and are easily handled and readily pourable. On warming or on long standing at room temperature, the plastisol gels as the plasticizer solvates the resin, but the gel has little physical integrity. When a plastisol is heated to a temperature of about 148.degree. to 177.degree. C., the plastisol is transformed to a homogeneous melt which, upon cooling to below 50.degree. C., results in a tough flexible product. The PVC resins made by emulsion polymerization are hard spheres of particle size between about 0.05 to 20 microns. They do not have the ability to absorb plasticizers. Therefore, a mixture containing, for example, 30% plasticizer and 70% PVC resin, produces a flowable liquid, known as plastisol. With certain plasticizers or resins, the plastisol may become a gelatinous mass under controlled conditions, and then may be used as a plastigel, for example, in the production of certain types of floor coverings.
It is also known to prepare transdermal delivery devices from polyvinyl chloride plastisol compositions, as disclosed in pending U.S. application Ser. No. 657,911, filed on Oct. 5, 1984 assigned to the same assignee as the present invention. Polyvinyl chloride generally is a stiff dry material which conforms poorly to the skin and delivers drug slowly.
General purpose PVC resins are made by mass and suspension polymerization process, and comprise the largest amount of PVC resins, and are used chiefly to make so-called 100% vinyl products by a variety of molding and extrusion techniques. Resins intended for flexible applications should have good uptake of plasticizer in a dry blending operation and contain more than 25% of a plasticizer system. PVC compounds that contain less than 25% plasticizers are referred to as semi-rigid compounds. The PVC resins manufactured by suspension and bulk polymerization are 50 to 200 microns in diameter, such as 100 to 500 microns in diameter, and are like sponges. They are capable of absorbing large amounts of plasticizers, so that even a 50% plasticizer, 50% PVC resin composition would result in a non-flowing, solid material.